The mechanistic basis of prostate cancer progression is poorly understood, and therapeutic options in these settings are limited, and only marginally effective. The present Program Project application is a multidisciplinary team effort designed to address these needs by elucidating fundamental mechanisms of prostate cancer growth (i), and credentialing novel molecular therapies for advanced disease, in vivo (ii). Our approach focuses on a prostate cancer signaling 'network' important for disease progression. This network connects three fundamental pathways of cellular homeostasis: mitochondrial control of cell survival by molecular chaperones, pleiotropic signaling by integrin adhesion receptors, and local regulation of gene expression in bone metastasis. Project 1 (Altieri) will dissect the function of mitochondria-localized Heat Shock Protein-90 (Hsp90) chaperones in survival of prostate cancer cells, Project 2 (Languino) will study the mechanism of prostate cancer progression mediated by a{v}B{6} integrin, and Project 3 (Stein and Lian) will elucidate the mechanistic requirements of Runx2-dependent gene expression in metastatic prostate cancer to the bone. Each project embeds preclinical evaluation of a novel class of network inhibitors in molecular and genetic models of localized and metastatic prostate cancer, in vivo. These agents include small molecule Hsp90 antagonists subcellularly targeted to mitochondria (Project 1), a function-blocking monoclonal antibody to a{v}B{6} (Project 2), and gene therapy silencing of Runx2 by short hairpin RNA (Project 3). All three projects are thematically integrated, rely on a long-standing track record of collaboration between the participating investigators, and share common experimental strategies, in vitro, and genetic disease models, in vivo. Three discovery-oriented Cores support equally the proposed experimental aims. Core A (Administration and Biostatistics: Altieri and Hsieh) will ensure programmatic integration, and provide biostatistics support for the preclinical studies. Core B (Animal Models: Bogdanov and Jones) will maintain quality control of the various genetic mouse models of prostate cancer, and provide state-of-the-art molecular imaging for analysis of tumor responses, in vivo. Core C (Pathology: Leav and Jiang) will oversee quantitative tissue analysis and evaluation of molecular biomarkers for pathway and target validation of network inhibitors, in vivo. The overall application is designed to merge molecular and translational prostate cancer research in a single, integrated and multidisciplinary platform. The overarching goal is to credential novel molecular therapies for patients with advanced and metastatic prostate cancer.